I. Research Objective:

Assess mortality on breast cancer survivors caused by cardiovascular disease (CVD) in women older than 17 years of age residing in Puerto Rico that are diagnosed with breast cancer (by microscopic confirmation) during the period of 2004-2019.

A. Datasets (available at the moment):

Cancer Registry Data: The initial selection is all women residents in PR diagnosed with breast cancer (by microscopic confirmation) during the period 2005-2019.

NCHS Mortality Data for years 2004-2019.

Census Population Estimates for years 2000-2023 for women residents in PR by age groups.

B. Analysis Proposal:

Below is the overall proposed analysis strategy to meet the study objectives:

  1. Descriptive characteristics of the study population

  2. Estimate Standardized Mortality Ratios (SMR’s) with confidence intervals (Poisson-based CI’s) on the study population. Proposed SMR definition: observed number of CVD deaths among breast cancer patients divided by the expected number of CVD deaths in the matched general female population in PR.

  3. Estimate Survival Curves, estimate Cumulative Incidence of Death (Cumulative Mortality) considering the effects of competing risks (Cardiac-related death vs Other/Breast Cancer-related death) using Competing Risks Regression (HRs).

II. Descriptive Analysis

A. Summary Counts

Table 1: Baseline Characteristics of Study Population

Table 1: Baseline Characteristics of Study Population
Characteristic All death causes
N = 27,238		 Alive
N = 18,943		 BC death
N = 4,595		 CVD death
N = 537
Treatment



    Surgery + Chemotherapy + Radiotherapy 6,139 (23%) 4,372 (23%) 1,168 (25%) 74 (14%)
    Surgery + Radiotherapy 5,811 (21%) 4,648 (25%) 426 (9.3%) 97 (18%)
    Surgery + Chemotherapy 3,273 (12%) 2,271 (12%) 723 (16%) 35 (6.5%)
    Chemotherapy + Radiotherapy 139 (0.5%) 41 (0.2%) 79 (1.7%) 1 (0.2%)
    Surgery Only 9,177 (34%) 6,312 (33%) 1,277 (28%) 272 (51%)
    Chemotherapy Only 477 (1.8%) 198 (1.0%) 206 (4.5%) 6 (1.1%)
    Radiotheraphy Only 70 (0.3%) 21 (0.1%) 34 (0.7%) 2 (0.4%)
    No treatment 972 (3.6%) 425 (2.2%) 362 (7.9%) 26 (4.8%)
    Unknown 1,180 (4.3%) 655 (3.5%) 320 (7.0%) 24 (4.5%)
Stage at Diagnosis



    Localized 15,520 (57%) 12,298 (65%) 1,225 (27%) 322 (60%)
    Distant 1,389 (5.1%) 361 (1.9%) 801 (17%) 15 (2.8%)
    Regional 8,727 (32%) 5,297 (28%) 2,215 (48%) 165 (31%)
    Unstaged 1,602 (5.9%) 987 (5.2%) 354 (7.7%) 35 (6.5%)
Age at Diagnosis



    0-17 0 (0%) 0 (0%) 0 (0%) 0 (0%)
    18-59 11,989 (44%) 9,184 (48%) 2,079 (45%) 57 (11%)
    60+ 15,243 (56%) 9,753 (51%) 2,516 (55%) 480 (89%)
    Unknown 6 (<0.1%) 6 (<0.1%) 0 (0%) 0 (0%)
ER Assay



    Positive 15,994 (59%) 12,198 (64%) 2,002 (44%) 279 (52%)
    Negative 4,102 (15%) 2,549 (13%) 1,069 (23%) 55 (10%)
    Other 2,234 (8.2%) 1,320 (7.0%) 457 (9.9%) 68 (13%)
    Unknown 4,908 (18%) 2,876 (15%) 1,067 (23%) 135 (25%)
PR Assay



    Positive 13,612 (50%) 10,532 (56%) 1,530 (33%) 239 (45%)
    Negative 6,325 (23%) 4,125 (22%) 1,504 (33%) 90 (17%)
    Other 2,282 (8.4%) 1,343 (7.1%) 472 (10%) 69 (13%)
    Unknown 5,019 (18%) 2,943 (16%) 1,089 (24%) 139 (26%)
HER2



    Positive 2,445 (9.0%) 1,814 (9.6%) 447 (9.7%) 20 (3.7%)
    Negative 12,916 (47%) 10,053 (53%) 1,633 (36%) 186 (35%)
    Other 9,407 (35%) 5,371 (28%) 2,085 (45%) 290 (54%)
    Unknown 2,470 (9.1%) 1,705 (9.0%) 430 (9.4%) 41 (7.6%)
Comorbidities



    3 or more comorbidites 126 (0.5%) 57 (0.3%) 21 (0.5%) 12 (2.2%)
    1-2 comorbidities 3,110 (11%) 2,185 (12%) 431 (9.4%) 83 (15%)
    No comorbidity 24,002 (88%) 16,701 (88%) 4,143 (90%) 442 (82%)
Myocardial Infarction



    Yes 53 (0.2%) 23 (0.1%) 7 (0.2%) 10 (1.9%)
    No 17,536 (64%) 13,089 (69%) 2,600 (57%) 266 (50%)
    Unknown 9,649 (35%) 5,831 (31%) 1,988 (43%) 261 (49%)
Congestive heart failure



    Yes 371 (1.4%) 213 (1.1%) 55 (1.2%) 31 (5.8%)
    No 17,218 (63%) 12,899 (68%) 2,552 (56%) 245 (46%)
    Unknown 9,649 (35%) 5,831 (31%) 1,988 (43%) 261 (49%)
Peripheral vascular disease



    Yes 506 (1.9%) 340 (1.8%) 70 (1.5%) 16 (3.0%)
    No 17,083 (63%) 12,772 (67%) 2,537 (55%) 260 (48%)
    Unknown 9,649 (35%) 5,831 (31%) 1,988 (43%) 261 (49%)
Cerebrovascular disease



    Yes 273 (1.0%) 159 (0.8%) 41 (0.9%) 12 (2.2%)
    No 17,316 (64%) 12,953 (68%) 2,566 (56%) 264 (49%)
    Unknown 9,649 (35%) 5,831 (31%) 1,988 (43%) 261 (49%)
Chronic pulmonary disease



    Yes 1,015 (3.7%) 685 (3.6%) 142 (3.1%) 33 (6.1%)
    No 16,574 (61%) 12,427 (66%) 2,465 (54%) 243 (45%)
    Unknown 9,649 (35%) 5,831 (31%) 1,988 (43%) 261 (49%)
Diabetes without chronic complication



    Yes 1,787 (6.6%) 1,251 (6.6%) 254 (5.5%) 47 (8.8%)
    No 14,744 (54%) 11,151 (59%) 2,219 (48%) 190 (35%)
    Unknown 10,707 (39%) 6,541 (35%) 2,122 (46%) 300 (56%)
Diabetes with chronic complication



    Yes 28 (0.1%) 12 (<0.1%) 9 (0.2%) 2 (0.4%)
    No 17,561 (64%) 13,100 (69%) 2,598 (57%) 274 (51%)
    Unknown 9,649 (35%) 5,831 (31%) 1,988 (43%) 261 (49%)
Health Region



    Noreste Metro 6,633 (24%) 4,538 (24%) 1,173 (26%) 142 (26%)
    Central Bayamon 4,341 (16%) 3,087 (16%) 677 (15%) 70 (13%)
    Oeste Aguadilla/Mayaguez 3,892 (14%) 2,656 (14%) 684 (15%) 82 (15%)
    Sureste Caguas 3,922 (14%) 2,788 (15%) 629 (14%) 66 (12%)
    Sur Ponce 3,840 (14%) 2,591 (14%) 740 (16%) 88 (16%)
    Norte Arecibo 3,389 (12%) 2,405 (13%) 506 (11%) 67 (12%)
    Este Fajardo 1,047 (3.8%) 710 (3.7%) 184 (4.0%) 22 (4.1%)
    County Unknown 174 (0.6%) 168 (0.9%) 2 (<0.1%) 0 (0%)
Note: Values are N (%), unless otherwise indicated.

Table 2: Summary statistics by mortality type

Table 2: Summary statistics by mortality type
Characteristic All death causes
N = 8,294		 BC death
N = 4,595		 CVD death
N = 537
Age at Diagnosis


    Mean(±SD) 65(±15) 61(±15) 74(±11)
    Median (Q1-Q3) 66 (55-76) 61 (51-72) 75 (67-82)
    Min-Max 18-104 18-103 35-101
Age at Death


    Mean(±SD) 70(±15) 65(±15) 79(±12)
    Median (Q1-Q3) 71 (59-81) 65 (55-75) 81 (72-88)
    Min-Max 21-107 21-104 41-103
Time to death (years)


    Mean(±SD) 4.5(±3.8) 3.7(±3.3) 5.6(±4.0)
    Median (Q1-Q3) 3.0 (2.0-7.0) 3.0 (1.0-5.0) 5.0 (2.0-8.0)
    Min-Max 0.0-18.0 0.0-17.0 0.0-17.0

B. Exploratory Data Analysis

Figure 1: Age distribution of study population

Figure 2: Age distribution of study population

Figure 3: Bar plots for procedures (surgery,chemotherapy,radiotherapy)

Figure 4: Bar plots for procedures (surgery,chemotherapy,radiotherapy)

Figure 5: Bar plots for procedures (surgery,chemotherapy,radiotherapy)

Figure 6: Bar plot for Comorbidity Index

Figure 7: Bar plots for ER, PR & HER2

Figure 8: Bar plots for ER by Vital Status

Figure 9: Bar plots for PR by Vital Status

Figure 10: Bar plots for HER2 by Vital Status

III. Survival Curves

Figure 11: Overall Mortality Survival Curve

Table 3: Overall Mortality Survival Confidence Intervals Table

5-year (95% CI) 10-year (95% CI) 15-year (95% CI)
61.85(61.01-62.72) 35.3(34.25-36.37) 14.54(13.39-15.8)
Values are n (%), unless otherwise indicated. Crude number and rate estimates of mortality from the study data. All-cause mortality estimated by Kaplan-Meier methods

Figure 12: CVD Specific Mortality Survival Curve

Table 4: CVD Specific Mortality Survival Confidence Intervals Table

5-year (95% CI) 10-year (95% CI) 15-year (95% CI)
45.07(41.05-49.48) 13.41(10.81-16.62) 1.3(0.62-2.72)
Values are n (%), unless otherwise indicated. Crude number and rate estimates of mortality from the study data. All-cause mortality estimated by Kaplan-Meier methods

Figure 13: Overall Mortality Survival Curve by Treatment

Figure 14: All Cause Mortality Survival Curve by Surgery Treatment

Table 5: All Cause Mortality Survival Confidence Intervals Table by Surgery Treatment

Treatment 5-year (95% CI) 10-year (95% CI) 15-year (95% CI)
Surgery + Chemotherapy + Radiotherapy 64.39(62.66-66.16) 39.32(37.14-41.63) 16.57(14-19.61)
Surgery + Radiotherapy 77.95(76.23-79.71) 48.56(46.05-51.2) 21.54(18.72-24.79)
Surgery + Chemotherapy 61.03(58.67-63.49) 34.44(31.38-37.8) 11.91(8.6-16.48)
Surgery Only 60.79(59.31-62.3) 31.95(30.25-33.75) 12.28(10.55-14.29)
Values are n (%), unless otherwise indicated. Crude number and rate estimates of mortality from the study data. All-cause mortality estimated by Kaplan-Meier methods

IV. Competing Risks

If the goal is to assess cardiac death mortality, both death related to breast cancer and other causes are competing events.

Figure 15: Cumulative incidence functions (1 = Cardiac death ; 2 = Other cause death)

Table 6: Cumulative Incidence of Death (CVD Death vs Other)

5-year (95% CI) 10-year (95% CI) 15-year (95% CI)
CVD Death 2.11(1.87-2.37) 4.52(4.1-4.97) 6.48(5.85-7.14)
Other Causes of Death 36.03(35.19-36.87) 60.19(59.12-61.24) 78.98(77.68-80.21)
Note: Values are n (%), unless otherwise indicated. CVD and BC mortality are estimated by Fine and Gray’s competing risk method.

Figure 16: Cumulative incidence functions (1 = Cardiac death ; 2 = Breast Cancer death, 3 = Other Cause death)

Table 7: Cumulative Incidence of Death (including BC mortality)
5-year (95% CI) 10-year (95% CI) 15-year (95% CI)
CVD Death 2.11(1.87-2.37) 4.52(4.1-4.97) 6.48(5.85-7.14)
BC Death 23.6(22.87-24.32) 34.39(33.46-35.33) 41.27(40.08-42.46)
Other Causes of Death 12.44(11.87-13.02) 25.79(24.88-26.71) 37.71(36.42-38.99)
Note: Values are n (%), unless otherwise indicated. CVD, BC mortality and Other Cause mortality are estimated by Fine and Gray’s competing risk method.

IV. Cumulative Incidence Curves for CVD Mortality

Figure 17: CIF for CVD Mortality by Treatment

Figure 18: CIF for CVD Mortality by Diagnosis

Figure 19: CIF for CVD Mortality by Comorbidity

Figure 20: CIF for BC Mortality by Comorbidity

Figure 21: Cumulative incidence curves for CVD and BC Mortality by Comorbidity

Figure 22: Cumulative incidence curves for CVD Mortality by Stage at Diagnosis

Figure 23: Cumulative incidence curves for BC Mortality by Stage at Diagnosis

Figure 24: Cumulative incidence curves for CVD and BC Mortality by Stage at Diagnosis

A. Competing Risks Regression

1. Subdistribution of Harzards

Table 8: Hazard ratios (95% CI) from Subdistribution Hazard Model for Cardiac Death

Characteristic HR1 95% CI1 p-value
StageAtDx


    Localized — —
    Distant 0.38 0.22, 0.65 <0.001
    Regional 0.80 0.66, 0.97 0.024
    Unstaged 0.87 0.60, 1.28 0.5
Comorb.cat


    Yes — —
    No 0.42 0.33, 0.54 <0.001
    Unknown 0.64 0.52, 0.79 <0.001
Procedure


    Surgery + Chemotherapy + Radiotherapy — —
    Surgery + Radiotherapy 1.41 1.04, 1.90 0.028
    Surgery + Chemotherapy 0.94 0.63, 1.40 0.8
    Chemotherapy + Radiotherapy 0.69 0.10, 4.94 0.7
    Surgery Only 2.39 1.84, 3.10 <0.001
    Chemotherapy Only 1.14 0.49, 2.63 0.8
    Radiotheraphy Only 3.24 0.74, 14.2 0.12
    No treatment 2.13 1.33, 3.42 0.002
    Unknown 2.06 1.25, 3.38 0.004
1 HR = Hazard Ratio, CI = Confidence Interval

Forest Plot of Hazard Ratios

Figure 25: Subdistribution HR (95% CI) by Stage at Diagnosis

Figure 26: Subdistribution HR (95% CI) by Treatment

Figure 27: Subdistribution HR (95% CI) by Comorbidity